The major cathepsin L secreted by the invasive juvenile Fasciola hepatica prefers proline in the S2 subsite and can cleave collagen

Juvenile-specific cathepsin proteases in Fasciola spp.: their characteristics and vaccine efficacies

“…Two juvenile cathepsin L proteases have been identified in F. hepatica, namely FhCL3 and FhCL4 (Harmsen et al 2004;Cancela et al 2008), and their sequences were identical to cathepsin L1G (FgCatL1G) and L1H (FgCatL1H) of F. gigantica, respectively (Cancela et al 2008;Sansri et al 2013). FhCL3 exhibited optimal activity and stability at neutral pH and could cleave collagen, but not immunoglobulin, suggesting its role in parasite migration through the liver (Table 1) (Corvo et al 2009;Robinson et al 2011). However, its F. gigantica orthologue, FgCatL1G, could digest several extracellular matrix proteins including collagen, laminin, and fibronectin and also cleaved immunoglobulin, suggesting its other role in immune evasion (Norbury et al 2011).…”

The Phylogeny, Structure and Function of Trematode Cysteine Proteases, with Particular Emphasis on the Fasciola hepatica Cathepsin L Family

“…Thus, a family of proteases with subtle, but important, amino acid changes within the enzyme`s active site cleft evolved (see below). [28][29][30] It has been suggested that these residue changes conferred Recently, we correlated the ability of FhCL2 to accommodate Pro in the S2 subsite with the capacity to cleave native collagen, which contains the repeat motif Gly-Pro-Xaa (where Xaa is any amino acid). 29 Since collagen is a major component of interstitial matrices, this property is likely to be important for disrupting cellular integrity making it easier for the parasite to migrate through host tissues.…”

“…29 Our biochemical and structural data on FhCL2 and that of Corvo et al on FhCL3 clearly demonstrate that both enzymes, like cathepsin K, cleave collagen within the triple helical regions. 30 However, both FhCL2 and FhCL3 can digest native collagen at neutral pH while degradation of collagen by cathepsin K requires acidic conditions. In humans, cleavage of collagen by cathepsin K is essential for bone remodelling.…”

“…In contrast, FhCL3 activity is vital for penetrating the host gut wall, while adult parasites which must penetrate and migrate through large host organs, including the liver, require FhCL2 activity for degrading collagen-rich interstitial matrices, both likely occurring under physiological pH. [29][30][31]35 …”

“…36 Mammalian lysosomal cathepsin Ls are active only at approximately pH 4.5, in keeping with the environment in which they function and are inherently unstable at neutral pH so that cellular damage due to leakage from the lysosome is avoided. 37 Interestingly, Corvo et al found WKH S+ SUR¿OH RI )K&/ WR EH LQ WKH QHXWUDO UDQJH ZLWK DQ RSWLPXP S+ RI 30 In contrast to FhCL1 that displays impressive stability at low pH, FhCL3 demonstrated only 35% of maximum activity at pH 5.5. 36 In terms of stability, FhCL3 retained 50% activity after 8 h at neutral pH and 37 $C.…”